Develop better bowel cancer treatments, via translational research, into new surgical techniques including robotics, biosensors and fluorescence guided surgery.

(i)Proposed Research and Leadership Programme This proposal addresses many of the recommendations included in the recent Royal College of Surgeons From Theory to Theatre report[1], which highlights the need for investment in surgical research and academic departments to increase translation of new techniques and technologies into surgical practice for the benefit of patients. The current 5 year programme draws on an expanding basic science research platform to undertake T1 translational first-inman research, which is the focus of the application, in preparation for T2 clinical translation in the future. Specifically, I would use an NIHR Research Professorship to undertake research which addresses translational gaps and to: a) accelerate the progress of Surgical Technologies and Stratified Surgery into clinical practice b) develop new translational surgical trials c) increase existing NIHR portfolio clinical trials activity d) further develop our academic clinical careers programme An overview of current and planned research activity is summarised in Figure 3, page 7ii. a) Accelerated translation of research into clinical practice: I am involved in a number of collaborative research projects developing new surgical technologies and stratified approaches for cancer surgery. Many of these projects are funded (Intra-corporeal robotics, NIHR/NEAT; Device-tissue interactions and Biosensors for surgical application, LTHT) or under consideration of funding (Intra-Abdominal Platform, Wellcome Trust). The majority of these projects will deliver devices ready for first-in-man (T1) translation within the timeframe of an NIHR Research Professorship. Figure 3 (page 7ii) summarizes the opportunities for translation of basic science into clinical practice; although a single arrow is used to denote translation for each work stream, in reality several translational opportunities will arise e.g. fluorescent-guided surgery may result in nanoparticles for use in clinical scenarios other than laparoscopic surgery. An NIHR Research Professorship would enable me to dedicate more time to those projects that need greater input to accelerate translation, and to secure any additional funding required. Some projects are at an earlier stage of development than others (e.g. metabolic targets for adjuvant therapy) although the underpinning research has been done to bring them to the stage of project grant application. In my current position, with 4.5 PAs dedicated to research, it is unlikely that I will have sufficient time to bring about translation of all these projects within the time scale indicated. A Clinical Lecturer to assist in delivery of this programme would be invaluable, and would provide an ideal opportunity for both clinical training and academic training in translational research methodology. b) Development of a new translational surgical trials As part of an NIHR Research Professorship, I would also wish to develop a new surgical trial and my preference would be to fast track my proposal for “Selective D2/D3 lymphadenectomy for colorectal cancer”. The hypothesis for this study is based on evidence that patients with colon cancer and lymph node metastasis benefit from a more radical D3 lymphadenectomy, rather than the standard D2 lymphadenectomy, with a 5-year survival advantage in the region of 27% [1,2] (Figure 1, page 7i).However, only 30% of colon cancer patients have lymph node disease (Dukes’ C) meaning that a universal policy of D3 lymphadenectomy is overtreatment for the majority, particularly in view of the additional morbidity from more radical resection. Given the limitations of preoperative radiological imaging in determining lymph node disease, a strategy to assess lymph node status at the time of operation is required. This will enable selection of patients for segmental resection with either D2 or D3 lymphadenectomy. The proposed study aims to evaluate a novel method to determine intraoperative lymph node status, utilizing a combination of patent blue V dye and 5-aminolevulinic acid (5-ALA). Patent blue V dye is non-specifically taken up in the lymphatic system and provides an overview of lymphatic anatomy, whilst 5-ALA is selectively taken up by cancer cells. Both patent blue V dye and 5-ALA are in clinical use, with established safety profiles. The concept is based on sentinel lymph node mapping, but with the benefit of 5-ALA to provide tumour specific fluorescence. Patients undergoing elective surgery for colon cancer will receive submucosal injection of patent blue V dye/5-ALA in the region of the cancer by colonoscopy, and then stratified to undergo either standard D2 lymphadenectomy or more radical D3 lymphadenectomy based on the likelihood of lymph node disease as determined by a combination of routine radiological imaging and intraoperative patent blue A period of optimization will be required, as although the use of patent blue V dye in sentinel lymph node mapping is well established, 5-ALA has only previously been successfully used for in oral form in patients with inoperable gastrointestinal cancer and enema form in patients with rectal cancer. Its application by submucosal injection for fluorescent lymph node detection is novel. A preliminary optimisation study is therefore proposed, to recruit 40 patients over a period of 12–18 months. This optimisation phase will take place in two centres Leeds and Dublin (the investigator in Dublin, Mr Ronan Cahill, has particular expertise in sentinel lymph node mapping). The findings will inform a formal prospective clinical trial. Sample size calculations have suggested that 200 patients will be required to detect a 16-18% difference in sensitivity and 13-16% difference in specificity between radiological imaging and intraoperative lymph node assessment. To enable 200 patients to be recruited over a period of 24 months it is planned to involve up to 5 centres. Centres will be selected on the basis of surgical proficiency in laparoscopic surgery, familiarity with translational research and good clinical practice, high volume for colon cancer, and expertise and resource in radiological imaging and histopathology. Given that cancers of the right and sigmoid colon account for over 50% of colon cancers and that the average high volume cancer centre will treat around 200 colon cancers per year, a figure of 200 patients over 24 months, or 20 patients per centre per annum, should be readily achievable. 7 i Although the above surgical trial would be my preferred new translational (T1) project to fast track with NIHR funding, I would also wish to develop a second trial during the Professorship. This trial would assess the role of robotics in facilitating segmental colectomy with D3 lymphadenectomy for colon cancer. D3 lymphadenectomy is technically challenging, particularly when performed within the constraints of laparoscopic surgery. To revert to open surgery for the purpose of performing a D3 lymphadenectomy would be a retrograde step. Instead, safe and reliable methods of undertaking laparoscopic D3 lymphadenectomy are needed. Particular care is required when dissecting at the origin of the major vascular structures to achieve central lymph node clearance (Figure 2). This anatomical region is full of vital structures and surgical inaccuracy can lead to life-threatening haemorrhage, visceral perforation, and vagal denervation resulting in debilitating diarrhoea. The da Vinci® robot is ideally suited to accurate operating in confined anatomical locations. I would therefore develop a surgical trial to assess the safety, efficacy, and cost-effectiveness of the da Vinci robot in segmental colectomy with D3 lymphadenectomy in colon cancer. Recent evidence suggests that robotic right hemicolectomy can achieve lymph node yields 22% greater than laparoscopic surgery, and comparable to the best open surgery[3]. Preliminary sample size calculations suggest that 100 patients per arm would be required to show a meaningful difference in lymph node yield between robotic and laparoscopic surgery at 80% power. If distance between the cancer and the high-tie (another maker of oncological clearance) is considered, then 80 patients per arm would be required to show a clinical difference at 90% power. It should therefore be possible to conduct such a trial within the same budget as the “Selective D2/D3 lymphadenectomy for colorectal cancer” study. I would draw upon existing collaborations established as a result of our MRC/EME ROLARR trial to recruit participating centers with good research track records, expertise in laparoscopic and robotic surgery, and high volume surgery for colon cancer. It is likely that such a trial would involve around 10 centres, at least 5 of which would be UK based, and could be delivered within 2-3 years of commencement. Both the above research proposals build on our strengths in Leeds. Close and productive working relationships are enjoyed between academic surgery, academic pathology under Professor Phil Quirke, the Clinical Trials and Research Unit under Professor Julia Brown and Health Sciences/Academic Unit of Health Economics. All parties share an interest in colorectal cancer, and their effective collaboration has been previously demonstrated to deliver high quality evidence for the NHS, which incorporates strong clinical trial design, patient and public involvement, and economic evaluation. c) Increase existing NIHR portfolio clinical trials activity An NIHR Research Professorship would enable me to dedicate more time to developing NIHR portfolio clinical trials activity at Leeds Teaching Hospitals NHS Trust. Although we already participate in a number of NIHR portfolio clinical trials (ROLARR, FIAT, CReST, eTHoS, FOxTROT), there is scope for increased participation. With the aid of WYCLRN and RTR funding, we have established a team of 2 research nurses and 1 data administration clerk to concentrate on this activity. Other trials that we would like to adopt include TREC, ROSSINI, PULMICC, and DREAMS.